Since congenital heart defects constitute an important health concern, and the relationship between exposure to environmental contaminants during early development and adult-onset of cardiovascular disease is not well understood, there is a clear need for the generation of models to explain the processes by which environmental contaminants contribute to cardiac malformation and heart failure. TCDD (2,3,7,8- tetrachlorodibenzo-p-dioxin) is an environmental contaminant known to pose significant health risks. For example, exposure to dioxins such as TCDD is associated with congenital heart disease. Research by the Peterson/Heideman group has revealed that the heart is a target organ for TCDD-induced developmental toxicity in zebrafish, and it's effects on the heart resemble hypoplastic left heart syndrome in humans. My preliminary results show for the first time in zebrafish that exposure to sublethal concentrations of TCDD during early development and juvenile stages results in cardiac toxicity that persists in adults. The overall goal of this work is to determine if persistent, heritable cardiac toxicity is induced by sublethal exposure to TCDD during early life stages. To accomplish this goal, I will use zebrafish to test three hypotheses. First, I will test the hypothesis that sublethal exposure to TCDD during embryonic development will cause endpoints of cardiac toxicity and changes in gene expression that are similar to those caused by lethal TCDD exposure. Information obtained from these studies will help us to understand the mechanisms by which early developmental exposure to TCDD induces hypoplastic heart syndrome and heart failure in zebrafish. Second, I will test the hypothesis that exposure to TCDD during early life and juvenile stages will result in cardiac toxicity that persists in adults. These results will enable us to develop models for correlating exposure to TCDD during early development with adult-onset of heart disease. Third, I will test the hypothesis that sublethal exposure to TCDD during early life and juvenile stages results in cardiac toxicity that is heritable, and that their offspring show reduced development, growth and survival associated with impaired cardiac health. I will use biochemical approaches to confirm that reduced health and survival of the F1 generation is not the result of TCDD exposure via maternal transfer. Results obtained will lay the foundation for determining whether TCDD can induce cardiac disease via epigenetic mechanisms. This work will significantly contribute to our understanding of how exposure to sublethal concentrations of TCDD during early life stages contributes to susceptibility to heart disease later in life. [unreadable] [unreadable] [unreadable]